Is ALX3 p.Pro335Leu (c.1004C>T) pathogenic?

ALX3 p.Pro335Leu (c.1004C>T) is classified Uncertain significance in ALX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0104%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ALX3 p.Pro335Leu (c.1004C>T)?

ALX3 p.Pro335Leu (c.1004C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ALX3 p.Pro335Leu (c.1004C>T) in the general population?

ALX3 p.Pro335Leu (c.1004C>T) is ultra-rare (popmax 0.0104%, nfe) (gnomAD).

What do computational predictors say about ALX3 p.Pro335Leu (c.1004C>T)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

ALX3 p.Pro335Leu

c.1004C>T · rs369347396 · VCV2530751

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0104%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.715	pathogenic-leaning
SaProt	LLR -6.29	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 793 bp · p 0.5 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0104% European (non-Finnish) · 117/1,120,660 alleles

Filtering AF 0.00887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00829%

Overall 0.00844% 126/1,493,494 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0104%	9,578
Remaining individualsnot grpmax-eligible	0.00877%	11,397
Finnishnot grpmax-eligible	0.00342%	29,240
African / African-American	0.00295%	33,894

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ALX3
Protein: p.Pro335Leu
Coding: c.1004C>T
MANE Select: NM_006492
dbSNP: rs369347396
Type: single nucleotide variant
Location: chr1:110060761 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.90

Full ALX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALX3 p.Pro250Leu Uncertain significance ★★ ⚠ same condition
ALX3 p.Pro40Ala Uncertain significance ★★ ⚠ same condition
ALX3 p.Ser131Arg Uncertain significance ★★ ⚠ same condition
ALX3 p.Tyr320Cys Uncertain significance ★★ ⚠ same condition
ALX3 p.Ala34Thr Uncertain significance ★ ⚠ same condition
ALX3 p.Ala65Thr Uncertain significance ★ ⚠ same condition
ALX3 p.Ala7Val Uncertain significance ★ ⚠ same condition
ALX3 p.Arg154His Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/alx3-p-pro335leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown